The development of new oligonucleotide drug formulations and other systems for administration of physiologically active oligonucleotides, such as RNA and DNA, or physiologically active peptides and proteins is driven by the need to achieve the desirable physiological effects. With respect to RNA oligonucleotides, many of them have been observed to be unstable in biological environment due to abundance of RNAses. Therefore they need to be stabilized or protected and/or delivered via systemic circulation either by infusion or repeated injection. In addition, oligonucleotides that have low molecular masses are expected to have short biological half-life due to their efficient removal from systemic circulation via kidneys. In addition, a fraction of these oligonucleotides are expected to be removed via reticuloendothelial uptake due to recognition by monocyte/macrophages or as a result of opsonization by complement components.
In part to circumvent rapid oligonucleotide degradation, either repeated injection or a continuous systemic infusion of oligonucleotides via a pump can be employed. Infusion strategy can be effective but may be impractical for outpatients requiring high levels of mobility, associated disadvantages of quality of life and potential intravenous (I.V.) line infections. Another approach is deliver oligonucleotides using implantable pump comprised of a capsule with a membrane allowing diffusion of the oligonucleotides, for example, at a desirable release rate. Due to lack of protection after release from these capsules, oligonucleotides will have difficulty reaching the target tissue before being degraded by RNAses or DNAses, taken up by non-target cells such as monocyte/macrophages or as a result of opsonization by complement components. Oligonucloetides can also be released into the extracellular space and distributed and degraded in the lymphatics. Overall concentration of oligonucleotides may be affected by local lymph node activity and the efficacy of lymph node drainage of the implantation site. There is also a potential of host reaction to capsule material but in general, this side effect is expected to be infrequent. The oligonucleotide release system can also be made biodegradable as a result of encapsulation or inclusion into degradable drug delivery vehicles or carriers, e.g. polymeric matrices, particles or membrane vesicles (liposomes). These delivery systems can be either implantable or injectable. Implantable oligonucleotide delivery systems can be placed under the epidermis where the components of the system are usually slowly degraded as a result of biological activity of surrounding cells (i.e. as a result of the release of enzymes degrading chemical bonds that hold these implants together).
U.S. Pat. No. 5,871,710 to Bogdanov et al. which hereby incorporated by reference discloses a biocompatible graft co-polymer adduct including a polymeric carrier, a protective chain linked to the polymeric carrier, a reporter group linked to the carrier or to the carrier and protective chain, and a reversibly linked Pt(II) compound for therapeutics. In Bogdanov et. al., the linkage between the reporter group and platinum is coordinate binding. However, Bogdanov et al. did not disclose an oligonucleotide delivery composition wherein the oligonucleotide to be delivered is hydrogen bonded to a complementary oligonucleotide covalently linked to the carrier and has a means of adjusting the release rates by varying the number of hydrogen bonding. As for example the hydrogen bonding of a U.S. Pat. No. 7,138,105 to Bolotin which hereby incorporated by reference discloses a biocompatible graft co-polymer comprising of a metal bridge flanked by two metal binding molecule wherein one of the metal binding molecule is part of or covalently linked to the therapeutic agent. The bridge provides a link between the carrier and therapeutic agent capable of binding metals. The linkage is by coordinate bonding and not by hydrogen bonding as in oligonucleotide binding to its complement, which is the subject of the present invention.
It has been over a decade since oligonucleotide such as siRNA and antisense RNA and DNA was discovered. However their therapeutic potential remains unrealized due to their rapid degradation and instability in vivo. In order, for oligonucleotide to be effective in inhibiting translation of specific genes, large doses are required which often induces toxicity to the organism being treated. The toxicity is not related to inhibition of translation of target genes but due to the overwhelming amount of materials being used (over 10 mg/kg). For over 10 years now, there is a long felt need to stabilized oligonucleotide in biological fluid to realize the promised potential of oligonucleotide therapies. There exists a need for a sustained release oligonucleotide delivery system that works for a wide range of oligonucleotides and where the release rate is readily controlled. The instant application discloses a biocompatible composition comprising of an oligonucleotide core that can reversibly bind an essentially complementary oligonucleotide, wherein the number of bases in the complementary oligonucleotide core can be altered to control the release rate of the reversibly bound oligonucleotide by increasing or decreasing the number of bases and thus the number of hydrogen bonds. The type and number of complementing bases determine the association constant (Ka) or dissociation constant (Kd) which then determines the amount of free oligonucleotide at any given condition. The concentration of free oligonucleotide and the further release of oligonucleotide from the carrier when the concentration of free oligonucleotide goes down is the result of the desire of the system to achieve the equilibrium constant (Ka or Kd).